We recently identified a line of transgenic mice that has a heritable form of polycystic disease (PKD) that closely resembles human infantile autosomal recessive PKD. The phenotype of the transgenic line arises from an insertional mutation caused by the integration of the transgene and is not related to expression of the transgene. In addition to closely mimicking human autosomal recessive PKD, this transgenic mutant line (Tg737) is unique in that we have been able to clone and characterize the DNA of the genetic locus. We expect to be able to directly analyze the mechanism by which a mutant gene participates in the development of PKD. Ultimately, DNA probes will be used to clone and map homologous genes in the human genome. Then, specific diagnostic tests could putatively be developed and genetic screening can be initiated. Different conventional therapies and newer methods of somatic cell gene therapy can be tested in the Tg737 mice. The SPECIFIC AIMS are: 1. To characterize the phenotype of the Tg737 mouse including the clinical, pathologic, and clinicopathologic changes associated with the PKD in Tg737 mouse. We will document the nature and progression of the renal and hepatic lesions and correlate the changes with clinical pathologic data. We will also evaluate the role of other genetic traits on the expression of the polycystic disease. 2. To further characterize the structure and expression of the wild-type gene within the region corresponding to the mutant locus in the Tg737 line. We will thoroughly characterize the structure of the cDNA clones we have isolated utilizing restriction mapping and nucleotide sequence analysis procedures. We will also utilize antibodies and probes to examine the expression of the Tg737 protein and mRNA in normal and Tg737 mouse tissues during development and the course of the disease. 3. A minigene construct prepared from the cloned wild-type copy of the Tg737 gene will be used to generate additional lines of transgenic mice in an attempt to "rescue" the phenotype in the mutant animals. 4. A full-length cDNA clone derived from the mouse Tg737 locus will be used as a probe to clone the homologous human gene, and then map it on the human genome.